The mechanism(s) underlying the initiation and progression of autoimmune diseases are not well understood. Clinical and epidemiologic evidence supports a role for viral infections. Postulated mechanisms include: molecular' mimicry (activation of autoreactive T cells secondarily by viral epitopes shared or cross-reactive with self antigens); epitope spreading (de novo activation of autoreactive T cells by sequestered antigens released secondary to self tissue destruction); and superantigens (non-specific stimulation of autoreactive T cells bearing particular VB receptors). Evidence for a viral etiology is particularly strong for multiple sclerosis (MS), a human CD4+ T cell mediated demyelinating disease associated with anti-myelin responses. The investigators have used the Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease model of MS to examine mechanisms of initiation and progression of virus-induced autoimmunity. TMEV is a natural mouse pathogen which establishes a life-long persistent CNS infection. Demyelination following infection of SJL mice with the wildtype BeAn strain of TMEV is initiated by virus-specific CD4+ Thl cells targeting virus persisting in CNS macrophages/microglia. Autoreactivity to the immunodominant myelin proteolipid protein epitope, PLP139-151, arises via epitope spreading two months post infection and plays a pathologic role in disease progression. To test the ability of molecular mimicry to initiate CNS demyelination, they engineered TMEV expressing PLP139-151 in the viral leader (PLP139-BeAn). SJL mice infected with PLP1 39-BeAn develop a severe, rapid-onset clinical demyelinating disease characterized by early activation of PLP1 39-151-specific T cells. They will test the hypothesis that CNS autoimmunity can be initiated by molecular mimicry induced by infection with a neurotropic virus. Aim 1 will further characterize PLP139-BeAn-induced disease by determining the pathologic role of PLP139-151-specific T cells (using tolerance and adoptive transfer) and the precursor frequency and temporal appearance of CD4+ and CD8+ TMEV- and myelin epitope-specific responses. Aim 2 will directly test the molecular mimicry hypothesis by assessing activation of autoreactive T cells1and clinical disease following infection with TMEV encoding molecular mimics of PLP139-151 naturally expressed by mouse hepatitis virus and H. influenzae. Relevant to human MS, Aim 3 will assess activation of autoreactive T cells and clinical disease induced by infection with TMEV encoding molecular mimics of the MS-associated MBP85 99 epitope naturally expressed by HSV, EBV, influenza A virus and Reovirus type 3 in HLA-DR2 transgenic mice. These studies should further our understanding of the potential role of molecular mimicry in MS etiology by defining activation requirements for autoreactive T cells primed by infection with a virus expressing molecular mimics of defined murine and human encephalitogenic myelin peptides and assessing their pathologic capacity.